Abstract Background: The prognosis of high grade gliomas (HGG) worsens with the age of the patients. We hypothesized that overexpression of senescence-related genes indicates a poorer prognosis. Materials and Methods: Frozen tumor samples from 60 patients of different ages (32 to 88 years) with the histologic diagnosis of HGG were macrodissected and arrayed on a custom version of the Affymetrix HG-U133 + GeneChip. There were 29 events (deaths) with a median survival time of 20 months. A set of 14 known senescence-associated genes (SAGs) including CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM1, IGFBP3, IL6, IL8, SAA4, TNFRSF11B, TNFSF11 and TP53 were the focus of the study (Campisi J. et al. PLoS Biology, 2008). An overall senescence score was generated using principal component analysis to reflect the combined effect of the senescence-associated gene signature. Pearson correlation and Cox proportional hazards regression were used to examine the association of each SAG and the senescence score with age at onset and overall patient survival. False discovery rate was used to adjust for multiple comparisons. Results: We found an age-related gradient in the senescence score representation of the combined SAGs (r = 0.40; p=0.0014). Ten SAGs were significantly correlated with age (false discovery rate at 5%): IGFBP3 (r=0.44), ICAM1 (r=0.40), IL6 (r=0.38), CDKN1A (r=0.35), TNFSF11 (r=0.34), TP53 (r=0.34), CXCL1 (r=0.31), CCL7 (r=0.30), COPG (r=0.29), and CSF2RB (r=0.29). The SAG signature was also correlated with poor prognosis (p=0.0098; median survival: 13 and 28 months, respectively, for high versus low senescence score). Two SAGs were significantly associated with patient survival: IL6 (14 versus 38 months) and COPG (13 versus 38 months). Conclusion: We report for the first time an SAG signature in HGG associated with age at onset and patient outcome. This signature composed of genes involved in cell cycle regulation, apoptosis, cell proliferation, and angiogenesis may define a more aggressive subtype of high-grade glioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-344.